Maintenance of platelet inhibition during antiplatelet therapy

ABSTRACT

A method for reducing or maintaining platelet inhibition in a patient by administering cangrelor prior to an invasive procedure is described. The method of this invention can be used for patients in need of antiplatelet therapy or at risk of thrombosis. The method can further be used in patients who were previously treated with long-acting platelet inhibitors without increasing the risk of excessive bleeding.

CROSS REFERENCE TO RELATED APPLICATIONS

This invention is a continuation of U.S. application Ser. No. 13/931,287filed on Jun. 28, 2013, which is a continuation-in-part of U.S.application Ser. No. 13/209,271 filed on Aug. 12, 2011, which is acontinuation-in-part of U.S. application Ser. No. 12/990,332 filed onAug. 15, 2011, which is a National Stage Entry of PCT/US09/043,820 filedon May 13, 2009, which claims priority to U.S. provisional applicationSer. No. 61/127,424 filed on May 13, 2008. Each of the above-referencedapplications is incorporated herein by reference.

FIELD OF THE INVENTION

The instant invention relates to the field of platelet inhibition, andin particular to methods of maintaining or reducing platelet activity inpatients undergoing an invasive procedure.

BACKGROUND OF THE INVENTION

Antiplatelet therapy has been shown to reduce clinical ischemic eventsand improve outcomes for acute coronary syndrome (ACS) patients.Currently, the approved antiplatelet products include aspirin andthienopyridines, such as clopidogrel and ticlopidine. One of the mostwidely prescribed thienopyridines is clopidogrel, which is also known asPlavix®.

Thienopyridines such as clopidogrel irreversibly inhibit P2Y₁₂receptors, which play an active role in platelet activation. In thenormal state, when blood vessels are damaged, platelet activationmediated by P2Y₁₂ receptors play an important role to arrest bleeding atthe site of injury. In a diseased state, platelet activation leads tovascular occlusion and ischemic damage. Thus, P2Y₁₂ receptor antagonistsplay a key role in antiplatelet therapy in assisting to prevent coronaryartery disease and for the immediate treatment of ACS and percutaneouscoronary intervention (PCI).

Physicians often prescribe dual antiplatelet therapy, which includeaspirin and a thienopyridine such as clopidogrel, as a first linetreatment for patients who have been diagnosed with ACS or who areshowing symptoms associated with ACS. Pending further examinations,these patients may continue with this treatment or receive othertreatments such as coronary artery bypass grafting (CABG) and PCI.Consistent with this practice, current American College ofCardiology/American Heart Association (ACC/AHA) guidelines recommendimmediate initiation of dual antiplatelet therapy of clopidogrel andaspirin after a patient is diagnosed with ACS. Similarly, patients whohave received a bare metal stent or drug-eluting stent are also put onthe dual clopidogrel and aspirin therapy for an extended period of timeto prevent an ischemic event. For instance, a post hoc analysis of ablinded, placebo-controlled trial suggests a benefit of plateletactivity inhibition in terms of decreased thrombotic events prior toCABG (Fox K A et. al, Circulation. 2004; 110; 1201-08). For manypatients, this dual antiplatelet therapy provides tremendous clinicalbenefits, and minimizes the risks of ischemic events, such as heartattack and stroke.

Dual antiplatelet therapy, however, has drawbacks. Cessation ofclopidogrel may increase the incidence of ischemic events in theshort-term due to a “rebound” effect of platelet activation (Brilakis ES et al, J Am Coll Cardiol. 2007 Jun. 5; 49(22): 2145-50; Ho P M et al,JAMA. 2008 Feb. 6; 299(5): 532-9).

In addition patients receiving dual antiplatelet therapy experience anincreased incidence of blood transfusions and bleeding complicationswhile undergoing surgery and other invasive procedures. This isparticularly true for ACS patients who often receive surgery, such asCABG and PCI, and other invasive procedures, such as implantation of abare metal stent (BMS) or drug-eluting stent (DES). Because aspirin andthienopyridines are irreversible, long-acting platelet antagonists,reversal of the inhibition of platelet function occurs only as newplatelets are generated; therefore, even after discontinuation, theireffect can last several days before being completely eliminated.

Thus, for patients under dual therapy who also require surgery such asCABG, sustained platelet inhibition poses an unacceptable risk ofbleeding. Consequently, it has been recommended by the ACC/AHA and theSociety of Thoracic Surgeons (STS) guidelines to cease thienopyridinetherapy prior to undergoing non-emergent cardiac surgical procedures tominimize bleeding risks. Hence, patients are often required to stop dualantiplatelet therapy and wait for five to seven days before any invasiveprocedures can be performed.

On the other hand, even though clopidogrel treatment prior to CABG doesincrease bleeding due to its irreversibility, platelet P2Y₁₂ inhibitionappears to prevent ischemic events in patients requiring CABG. As aresult, physicians often face the difficult choice of discontinuingclopidogrel and aspirin prior to surgery and risking a potentialischemic event in the unprotected perioperative period or delayingsurgery until the time at which clopidogrel is no longer required.

Currently, no ultra short-acting platelet inhibitors are available thatallow maintenance of platelet inhibition before an invasive procedurewithout increasing bleeding complications at the time of the invasiveprocedure. Potentially, effective platelet inhibition with an ultrashort-acting platelet inhibitor during the period of clopidogrelwithdrawal may protect patients from ischemic events and also preservenormal hemostasis at the time of surgery.

Therefore, a need exists for a new therapy for patients who areundergoing surgery (this includes therapy prior to, during, and post) orother invasive procedures, and who have a need for antiplatelet therapy.This new therapy should maintain platelet inhibition at acceptablelevels while allowing for rapid restoration of platelet function afterdiscontinuation, thereby “bridging” patients to their surgicalprocedures without increasing the risk of bleeding complications.

In addition, a need exists for a new therapy for patients who, forwhatever reason, cannot be administered thienopyridines, such asclopidogrel or Plavix®, or cannot receive orally administeredantiplatelet therapies.

SUMMARY OF THE INVENTION

As shown herein, the present invention describes compositions andmethods of maintaining or reducing platelet activity in a patient priorto the patient undergoing an invasive procedure by administering aneffective amount of short-acting P2Y₁₂ inhibitor.

In one aspect of this invention methods are described for administeringan effective amount of a short-acting P2Y₁₂ inhibitor to maintain orreduce platelet activity in a patient before an invasive procedure, in apatient previously treated with long-acting irreversible plateletinhibitors without an increased risk in bleeding.

In a related embodiment of this method, other therapeutic agents areadministered concurrently with the reversible, short-acting P2Y₁₂inhibitor.

In another related embodiment of this method, the risk of bleeding isnot increased.

In another aspect of this invention, a short-acting P2Y₁₂ inhibitor isused to maintain or reduce platelet activity in a patientperioperatively where oral antiplatelet therapy is contraindicated. Thereversible, short-acting P2Y₁₂ inhibitor can be administered to apatient as a bolus and/or a continuous intravenous infusion.

In another aspect of this invention, methods are described where aneffective amount of a short-acting P2Y₁₂ inhibitor is administered tosufficiently reduce or maintain at least 60% platelet inhibition orP2Y12 reaction units (PRU) values less than 240 prior to the patientundergoing an invasive procedure.

In a related embodiment to this method, the short-acting P2Y₁₂ inhibitoris discontinued thereby allowing platelet activity to return topre-administration levels as measured by PRU being greater than 240.

In yet another aspect of the present invention, methods are describedfor administering a reversible, short-acting P2Y₁₂ inhibitor to apatient who was previously administered a thienopyridine, and ceasingadministration of the short-acting P2Y₁₂ inhibitor wherein the PRUlevels are similar to pre-administration levels of the short-actingP2Y₁₂ inhibitor, prior to said patient undergoing an invasive procedure.

In another aspect of this invention, a method of treating or preventingthrombosis is described by administering a short-acting P2Y₁₂ inhibitorto a patient previously treated with a long-acting irreversible plateletinhibitor, where the risk of bleeding is not increased.

In another aspect of this invention, an intravenous pharmaceuticalcomposition of cangrelor is described for maintaining or reducingplatelet inhibition.

In another aspect of this invention, a method for preparing anintravenous cangrelor composition for inhibiting platelet activity bycombining cangrelor with mannitol, sorbitol and intravenouslyadministrable excipient for maintaining PRU values at a certain level.

Aspects of the present invention relate to a method of transitioning apatient from administration of cangrelor during PCI to administration ofcangrelor in preparation for surgery, or a method of maintaining reducedplatelet activity in a patient who is transitioning from administrationof cangrelor during PCI to administration of cangrelor in preparationfor surgery, or a method of maintaining P2Y₁₂ inhibition in a patientwho is transitioning from administration of cangrelor during PCI toadministration of cangrelor in preparation for surgery. These methodsmay comprise (1) administering a PCI dosing regimen, wherein the PCIdosing regimen comprises administering intravenously a 30 μg/kg bolus ofcangrelor before the start of PCI, and administering intravenously acontinuous infusion of cangrelor at an infusion rate of 4 μg/kg/minafter administration of the bolus; (2) discontinuing the administrationof the PCI dosing regimen; and (3) administering a bridge dosingregimen, wherein the bridge dosing regimen comprises administeringintravenously a continuous infusion of cangrelor at an infusion rate of0.75 μg/kg/min.

Aspects of the present invention further relate to a method oftransitioning a patient from administration of cangrelor in preparationfor surgery to administration of cangrelor during PCI, or a method ofmaintaining reduced platelet activity in a patient who is transitioningfrom administration of cangrelor in preparation for surgery toadministration of cangrelor during PCI, or a method of maintaining P2Y₁₂inhibition in a patient who is transitioning from administration ofcangrelor in preparation for surgery to administration of cangrelorduring PCI. These methods may comprise (1) administering a bridge dosingregimen, wherein the bridge dosing regimen comprises administeringintravenously a continuous infusion of cangrelor at an infusion rate of0.75 μg/kg/min; (2) discontinuing the administration of the bridgedosing regimen; and (3) administering a PCI dosing regimen, wherein thePCI dosing regimen comprises administering intravenously a 30 μg/kgbolus of cangrelor before the start of PCI, and administeringintravenously a continuous infusion of cangrelor at an infusion rate of4 μg/kg/min. In another embodiment, the method may comprise (1)administering a bridge dosing regimen, wherein the bridge dosing regimencomprises administering intravenously a continuous infusion of cangrelorat an infusion rate of 0.75 μg/kg/min; (2) discontinuing theadministration of the bridge dosing regimen; and (3) administering a PCIdosing regimen, wherein the PCI dosing regimen comprises administeringintravenously a continuous infusion of cangrelor at an infusion rate of4 μg/kg/min.

BRIEF DESCRIPTION OF THE FIGURES

Understanding of the present invention will be facilitated byconsideration of the following detailed description of the embodimentsof the present invention taken in conjunction with the accompanyingdrawings, in which like numerals refer to like parts and in which:

FIG. 1 is a graphical presentation of the percent inhibition ofadenosine diphosphate (ADP)-induced platelet aggregation and effect onbleeding time;

FIG. 2 is a flow chart of the time periods through which the presentinvention is performed;

FIG. 3 is a flow chart of a study demonstrating an exemplary method;

FIGS. 4-1 and 4-2 show a table of the studied assessments by time point;

FIG. 5 shows a comparison of PRU responses versus cangrelorconcentration for patients receiving a PCI dosing regimen and forpatients receiving a bridge dosing regimen;

FIG. 6 shows a simulated range of PRU responses for a male patient, 62years old and weighing 90 kg, with intravenous (IV) bolus loading dosefor PCI, transitioning from the bridge dosing regimen to the PCI dosingregimen (the shaded areas are the confidence intervals about the linesand the dashed line is the cut-off PRU value of 208, associated highsensitivity and specificity for the presence of P2Y₁₂ inhibition);

FIG. 7 shows a simulated range of PRU responses for a male patient, 62years old and weighing 90 kg, with no IV bolus loading dose for PCI,transitioning from the bridge dosing regimen to the PCI dosing regimen(the shaded areas are the confidence intervals about the lines and thedashed line is the cut-off PRU value of 208, associated high sensitivityand specificity for the presence of P2Y₁₂ inhibition);

FIG. 8 shows a simulated range of PRU responses for a female patient, 66years old and weighing 60 kg, with IV bolus loading dose for PCI,transitioning from the bridge dosing regimen to the PCI dosing regimen(the shaded areas are the confidence intervals about the lines and thedashed line is the cut-off PRU value of 208, associated high sensitivityand specificity for the presence of P2Y₁₂ inhibition);

FIG. 9 shows a simulated range of PRU responses for a female patient, 66years old and weighing 60 kg, with no IV bolus loading dose for PCI,transitioning from the bridge dosing regimen to the PCI dosing regimen(the shaded areas are the confidence intervals about the lines and thedashed line is the cut-off PRU value of 208, associated high sensitivityand specificity for the presence of P2Y₁₂ inhibition);

FIG. 10 shows a simulated range of PRU responses for male patient, 62years old and weighing 90 kg, transitioning from the PCI dosing regimento the bridge dosing regimen (the shaded areas are the confidenceintervals about the lines and the dashed line is the cut-off PRU valueof 208, associated high sensitivity and specificity for the presence ofP2Y₁₂ inhibition);

FIG. 11 shows a simulated range of PRU responses for female patient, 66years old and weighing 60 kg, transitioning from the PCI dosing regimento the bridge dosing regimen (the shaded areas are the confidenceintervals about the lines and the dashed line is the cut-off PRU valueof 208, associated high sensitivity and specificity for the presence ofP2Y₁₂ inhibition).

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for the purpose of clarity, many other elements found in typicalantiplatelet therapies. Those of ordinary skill in the art willrecognize that other elements and/or steps are desirable and/or requiredin implementing the present invention. However, because such elementsand steps are well known in the art, and because they do not facilitatea better understanding of the present invention, a discussion of suchelements and steps is not provided herein. The disclosure herein isdirected to all such variations and modifications to such elements andmethods known to those skilled in the art. Furthermore, the embodimentsidentified and illustrated herein are for exemplary purposes only, andare not meant to be exclusive or limited in their description of thepresent invention.

The present invention provides a method for inhibiting plateletreactivity in patients prior to undergoing an invasive procedure.

The methods described in the present invention maintains plateletinhibition at acceptable and targeted levels, while allowing for rapidrestoration of platelet function after discontinuation of the drugtherapy so that patients may undergo invasive procedures withoutincreasing the risk of bleeding complications.

The described methods can be used for patients in need of treatment toreduce or maintain platelet inhibition. Preferably the described methodscan be used in patients at risk of thrombotic events. More preferablythe embodiments of the present invention are directed to patientsdiagnosed with symptoms of stable or unstable angina, vascular ischemicevents, atherosclerosis, acute coronary syndrome, as well asST-elevation myocardial infarction (STEMI) or non-ST segment elevationmyocardial infarction (N-STEMI). The described methods can also be usedfor patients having previously received a stent, such as a bare metalstent or a drug-eluting stent, for the treatment or prevention of stentthrombosis. While the present invention is generally targeted for usewith human patients, the described methods can be used on any livinganimal.

The present invention further provides a method for reducing ormaintaining adequate P2Y₁₂ inhibition with rapid reversibility upondiscontinuation of long-acting irreversible platelet inhibitors prior topatients undergoing invasive procedures without increasing the risk ofbleeding complications.

Definitions

Long-acting P2Y₁₂ inhibitors refer to compounds which inhibit P2Y₁₂receptor activities, having a slow on-set and long eliminationhalf-life. Examples of long-acting P2Y₁₂ inhibitors are typicallyformulated as oral dosage forms. One example of long-acting P2Y₁₂inhibitor is long-acting irreversible P2Y₁₂ inhibitors. Examples oflong-acting irreversible P2Y₁₂ inhibitors include thienopyridines.Examples of thienopyridines include, without limitation, clopidogrel,ticloridine, and prasugrel and such other compounds having similarproperties. Clopidogrel is a pro-drug that requires metabolism forconversion to the active metabolite.

Short-acting reversible, P2Y₁₂ inhibitors refer to compounds whichinhibits P2Y₁₂ receptor activities, having a fast onset time and arelatively short metabolism rate as compared to those ofthienopyridines. Examples of a short-acting, reversible P2Y₁₂ inhibitorinclude, without limitations, cangrelor, ticagrelor and PRT060128. Itshould be noted that the present invention is not limited to theseexamples. Additional compounds that have similar properties may also beused in the present invention.

One particularly preferred example of a reversible, short-acting P2Y₁₂inhibitor is cangrelor. Cangrelor is a potent, direct, and reversibleantagonist of the platelet P2Y₁₂ receptor. Cangrelor has a half-life ofapproximately less than 10 minutes, allowing for a return to normalplatelet function in a very short period of time upon discontinuation ofthe drug. By reducing the need for a compound to be metabolized foractivity, and by having a relatively short half-life, reversible,short-acting P2Y₁₂ inhibitors are considered “reversible,” meaning thatfull platelet functionality may return rather quickly as compared tothienopyridines.

The binding of cangrelor to the P2Y₁₂ receptor inhibits plateletactivation as well as aggregation when mediated in whole or in part viathis receptor. Cangrelor can be derived completely from syntheticmaterials, and is an analogue of adenosine triphosphate (ATP). ATP is anatural antagonist of the P2Y₁₂ receptor sites and is found in humans.

The chemical structure for cangrelor is depicted below as Formula I.

Cangrelor is clinically well tolerated and safe and has no drug-druginteraction with aspirin, heparin or nitroglycerin. Unlike orally dosedthienopyridines, cangrelor can be administered intravenously and bindsdirectly to P2Y₁₂ receptor sites of platelets. In each of theembodiments of the present invention, the term “cangrelor” encompassesthe compound of Formula I as well as tautomeric, enantiomeric anddiastereomeric forms thereof, and racemic mixtures thereof, otherchemically active forms thereof, and pharmaceutically acceptable saltsof these compounds, including a tetrasodium salt. These alternativeforms and salts, processes for their production, and pharmaceuticalcompositions comprising them, are well known in the art and set forth,for example, in U.S. Pat. No. 5,721,219. Additional disclosure relevantto the production and use of cangrelor may be found in U.S. Pat. Nos.5,955,447, 6,130,208 and 6,114,313, as well as in U.S. Appln.Publication Nos. 2006/0270607 and 2011/0112030.

Invasive procedures means any technique where entry to a body cavity isrequired or where the normal function of the body is in some wayinterrupted by a medical procedure and/or treatment that invades(enters) the body, usually by cutting or puncturing the skin and/or byinserting instruments into the body. Invasive procedures can includeCABG, orthopedic surgeries, urological surgeries, PCI, other generalinvasive procedures, such as endarterectomy, renal dialysis,cardio-pulmonary bypass, endoscopic procedures or any medical, surgical,or dental procedure that could result in excessive bleeding orhemorrhage to the patient.

Perioperative means the period of a patient's invasive procedure whichcan occur in hospitals, surgical centers or health care providers'offices. Perioperative includes admission, anesthesia, surgery, torecovery.

Thrombosis is the formation of a blood clot (thrombus) inside a bloodvessel obstructing the flow of blood through the circulatory system.When a blood vessel is injured, the body uses platelets and fibrin toform a blood clot to prevent blood loss. Some examples of the types ofthrombosis include venous thrombosis which includes deep veinthrombosis, portal vein thrombosis, renal vein thrombosis, jugular veinthrombosis, Budd-Chiari syndrome, Paget-Schroetter disease, cerebralvenous sinus thrombosis, cerebral venous sinus thrombosis and arterialthrombosis which includes stroke and myocardial infarction.

Dosage and Administration

As used herein, the terms “dose”, “dosage”, “unit dose”, “unit dosage”,“effective dose”, “effective amount” and related terms refer tophysically discrete units that contain a predetermined quantity ofcangrelor, calculated to produce a desired therapeutic effect. Theseterms are synonymous with the therapeutically effective amounts andamounts sufficient to achieve the stated goals of the methods disclosedherein.

When administered as an IV formulation, a pharmaceutical compositioncomprising cangrelor may be administered as a bolus, as a continuousinfusion, or as a bolus followed by a continuous infusion. Whenadministered as a bolus, a dose of about 5, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 μg/kg cangrelor, ormore, is administered to the patient. In preferred embodiments, betweenabout 20 μg/kg and about 40 μg/kg cangrelor is administered, morepreferably about 30 μg/kg. When administered as a continuous infusion,cangrelor may be administered at about 0.1, 0.5, 0.75, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, 30 μg/kg/min, or more to the patient. Inpreferred embodiments, between about 0.1 and about 5 μg/kg/min cangreloris administered, more preferred is administration of cangrelor in therange of about 0.5 μg/kg/min to about 2 μg/kg/min. Even more preferredis a dosage range of cangrelor at about 0.5 μg/kg/min to about 1μg/kg/min. The skilled artisan will understand that different bolus andintravenous dosages from those set forth here may be administered basedon the particular characteristic of the patient. Thus, the dosage amountcan be varied from the dosage amount presently described, however, thedosage given must be sufficient to reduce or maintain the PRU valuesbelow about 240 as measured by VerifyNow®.

In addition, the skilled artisan will understand that the exact amountof reversible short-acting P2Y₁₂ inhibitor to be administered to apatient will vary depending on the degree of platelet activityinhibition that is sought. For example, the amount of reversibleshort-acting P2Y₁₂ inhibitor to be administered to a patient during aninvasive procedure that will result in bleeding may be much less thanthe amount that would be administered when such a procedure is not beingperformed.

The dosage of the reversible short-acting P2Y₁₂ inhibitor may beadministered as a continuous intravenous infusion or it may beadministered in discrete doses, such as between 1 and 48 doses, or more,per 24 hour period. The dosage of the reversible short-acting P2Y₁₂inhibitor may vary over time, with a lower dosage being initiallyadministered, followed by an increased dosage for a sustained period oftime, with an optional decrease in the dosage prior to completecessation of administration of the reversible short-acting P2Y₁₂inhibitor. Such a dosing regime may be used in conjunction with theconcurrent cessation of thienopyridine and/or aspirin treatment andbeginning of reversible short-acting P2Y₁₂ inhibitor. Such dosing regimecan also ensure a constant level of platelet activity inhibition.

In other forms, a reversible, short-acting P2Y₁₂ inhibitor can beadministered at a daily dose of from 0.1 mg to 1000 mg, which may be individed doses, e.g., up to 6 times per day.

The total amount of reversible, short-acting P2Y₁₂ inhibitor that may beadministered to a subject may be between about 0.01 and 1000 mg per 24hour period, with exemplary totals of about 0.5, 0.75, 1.0, 1.25, 1.5,1.75, 2.0 and 2.5 mg per 24 hour period.

In each of the embodiments where the pharmaceutical composition isadministered as continuous intravenous infusion, the infusion maycontinue for at least about 2 days to about 7 days. The skilled artisanwill understand that the period of time over which the pharmaceuticalcomposition is administered may be shorter or longer than the indicatedtimes due to the particular characteristics of a patient. Administrationof a reversible, short-acting P2Y₁₂ inhibitor can be made several daysto several hours prior to the invasive procedure. One example is toadminister a reversible, short-acting P2Y₁₂ inhibitor about 7 days toabout 1 hour prior to an invasive procedure. To maintain plateletinhibition, the reversible short-acting P2Y₁₂ inhibitor should beadministered within about 2 days to about 7 days of ceasingadministration of the long-acting platelet inhibitor. A further exampleis to administer the reversible short-acting P2Y₁₂ inhibitor withinabout 3 days of ceasing administration of the long-acting plateletinhibitor. Discontinuation of the reversible short-acting P2Y₁₂inhibitor can be performed about 1 to 6 hours before a surgicalprocedure. It should be noted that the duration for administering areversible, short-acting P2Y₁₂ inhibitor often vary depending on whichreversible, short-acting P2Y₁₂ inhibitor is used and the particularcharacteristic of the patient. One skilled in the art can vary theduration of administration so long as platelet inhibition as measured byVerifyNow® is below about 240.

Reversible, short-acting P2Y₁₂ inhibitors, such as cangrelor, ticagreloror PRT060128, can be administered using any of the various methods anddelivery systems known to those skilled in the art. The administeringcan be performed, for example, intravenously, orally, via implant,transmucosally, transdermally, intramuscularly, intrathecally, andsubcutaneously. According to one preferred embodiment, a reversible,short-acting P2Y₁₂ inhibitor may be administered intravenously. It iscontemplated that the reversible, short-acting P2Y₁₂ inhibitor can beadministered intravenously in accordance with the present inventionduring surgery, when the patient is comatose, or any other such scenariowhere the oral administration of the inhibitor is prohibited.

In the case of administering the therapy prior to surgery in accordancewith one embodiment of the present invention, such use allows patientsto undergo surgery or other invasive procedures without excessiveperioperative bleeding. For example, as described herein, cangrelorinfusion can maintain platelet inhibition levels of approximatelygreater than or equal to about 60% after discontinuation of clopidogrelwithout an increase in bleeding risk and before the invasive procedurebegins.

In addition to the pharmaceutical compositions of the present inventioncomprising cangrelor, the skilled artisan will understand thatadditional therapeutic agents may be used in combination with cangrelor.By way of non-limiting examples, compounds such as aspirin, bivalirudin,unfractionated heparin, low molecular weight heparin, fondaprinuxsodium, warfarin, coumarins, thrombolytics such as streptokinase,alteplase, reteplase, urokinse, tenecteplase, glycoprotein IIb/IIIainhibitors such as eptifibatide, abciximab, tirofiban, orantifibrinolytic agents such as epsilon amino-caproic acid, andtranexamic acid, can be used as concomitant medications.

Measurement of Platelet Activity

Assessment of platelet function can be determined by use of theVerifyNow® assay of which the System User Manual (Accumetrics, SanDiego, Calif., 2009) is incorporated by reference in its entirety. TheVerifyNow® P2Y12 assay is a point of care device for the assessment ofthe level of inhibition of platelet activation specifically designed forpatients exposed to thienopyridines. It should be understood that anyassay system for determining levels of inhibition of platelet activationcan be used, as understood by those having skill in the art. Bloodsamples for the VerifyNow® P2Y12 assay can be collected into GreinerBio-One Vacuette partial fill blood collection tubes (2 mL fill volume)containing 3.2% citrate, or by other suitable means.

The VerifyNow® P2Y12 assay is a rapid platelet-function cartridge-basedassay that activates platelets using ADP, but also uses prostaglandin E1to suppress the ADP-induced P2Y1-mediated increase in intracellularcalcium levels to increase the specificity of the test for inhibition ofthe P2Y₁₂ receptor. The test cartridge contains a lyophilizedpreparation of human fibrinogen coated beads, platelet agonist, bufferand preservative. Fibrinogen-coated microparticles are used to bind toavailable platelet receptors. When the activated platelets are exposedto the fibrinogen-coated microparticles, agglutination occurs inproportion to the number of available platelet receptors. Thewhole-blood citrate mixture is added to the cartridge, and agglutinationbetween platelets and coated beads is recorded. The VerifyNow® P2Y12device is a turbidimetric optical detection system, which measuresplatelet induced aggregation as an increase in light transmittance.VerifyNow® P2Y12 testing can be used at any time point as describedherein to assess the level of inhibition of platelet activity.

Assay results are expressed in PRU (VerifyNow® System User Manual(Accumetrics, San Diego, Calif., 2009)). High platelet reactivity, asassessed by VerifyNow® P2Y12 assay was defined as a PRU value greaterthan 240. The lower the PRU value, the greater the inhibition of theP2Y₁₂ receptor resulting in reduction of the platelet activity. For themethods described in this invention, the PRU level is preferablymaintained during the period of cangrelor administration at 240 or less.In a preferred embodiment of the present invention, the dose ofcangrelor was 0.75 μg/kg/min. This dose was maintained for about 2 toabout 7 days. PRU values in the patients were less than or equal to 240.

It would be understood by those skilled in the art that increasing theconcentration of cangrelor infusion will result in a decrease in PRUvalues and an increase in the percent platelet inhibition. It istherefore preferred to measure PRU values during the course of cangrelorinfusion.

Pharmaceutical Compositions

In each aspect and embodiment of the present invention, short-actingreversible platelet inhibitor is administered to a patient in the formof a pharmaceutical composition comprising the active ingredient and,optionally, a pharmaceutically acceptable carrier, diluent and/orexcipient. Thus, the present invention encompasses a pharmaceuticalcomposition comprising cangrelor, and a pharmaceutically acceptablecarrier, diluent and/or excipient.

Suitable carriers and diluents are well known to those skilled in theart and include saline, such as 0.9% NaCl, buffered saline, dextrose(e.g., 5% dextrose in water), water, Water-for-Injection (WFI),glycerol, ethanol, ringer's solution, propylene glycol, polysorbate 80(Tween-80), 0.002% polysorbate 80 (Tween-80), poly(ethylene)glycol 300and 400 (PEG 300 and 400), PEGylated castor oil (e.g. Cremophor EL),poloxamer 407 and 188, a cyclodextrin or a cyclodextrin derivative(including 2-hydroxypropyl)-cyclodextrin HPCD) and(2-hydroxyethyl)-cyclodextrin, hydrophilic and hydrophobic carriers, andcombinations thereof. Hydrophobic carriers include, for example, fatemulsions, lipids, PEGylated phospholipids, polymer matrices,biocompatible polymers, lipospheres, vesicles, particles, and liposomes.Excipients included in a pharmaceutical composition have differentpurposes depending, for example, on the nature of the drugs, and themode of administration. Examples of generally used excipients include,without limitation: stabilizing agents, solubilizing agents andsurfactants, buffers, antioxidants and preservatives, tonicity agents,bulking agents, lubricating agents, emulsifiers, suspending or viscosityagents, inert diluents, fillers, disintegrating agents, binding agents,wetting agents, lubricating agents, antibacterials, chelating agents,sweeteners, perfuming agents, flavouring agents, coloring agents,administration aids, and combinations thereof.

The pharmaceutical composition may contain common carriers andexcipients, such as cornstarch or gelatin, lactose, sucrose,microcrystalline cellulose, kaolin, mannitol, sorbiton, dicalciumphosphate, sodium chloride, alginic acid, croscarmellose sodium, andsodium starch glycolate.

The pharmaceutical compositions of the present invention may beformulated, for example, for oral, sublingual, intranasal, intraocular,rectal, transdermal, mucosal, topical or parenteral administration.Parenteral modes of administration include without limitation,intradermal, subcutaneous (s.c., s.q., sub-Q, Hypo), intramuscular(i.m.), intravenous (i.v. or IV), intraperitoneal (i.p.),intra-arterial, intramedulary, intracardiac, intra-articular (joint),intrasynovial (joint fluid area), intracranial, intraspinal, andintrathecal (spinal fluids). Any known device useful for parenteralinjection or infusion of drug formulations can be used to effect suchadministration. In noted aspects and embodiments of the presentinvention, administration of the pharmaceutical compositions is viaparenteral administration, preferably intravenous administration.

In IV administration, a sterile formulation of the pharmaceuticalcompositions of the present invention and optionally one or moreadditives, including solubilizers or surfactants, can be dissolved orsuspended in any of the commonly used intravenous fluids andadministered by infusion. Intravenous fluids include, withoutlimitation, isotonic infusion media such as physiological saline, 0.9%NaCl, phosphate buffered saline, 5% dextrose in water, 0.002%polysorbate 80 (Tween-80) in water or Ringer's solution.

Pharmaceutical compositions comprising cangrelor of the presentinvention include pharmaceutical compositions comprising from about 0.1to about 50 mg/ml of cangrelor. Particular examples of pharmaceuticalcompositions comprising cangrelor include the following: (i) cangrelorat a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10mg/mL in 0.9% NaCl; and (ii) cangrelor at a concentration of about 0.1,0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 5% dextrose in water. Thepharmaceutical composition may further comprise a pharmaceuticallyacceptable carrier or diluent such as sorbitol and mannitol.

One method for preparing a cangrelor composition includes dissolving 50mg lyophilized cangrelor or its pharmaceutically acceptable salt byinjecting 5 ml sterile water into a 10 ml vial containing cangrelor orits pharmaceutically acceptable salt thereof, preparing an intravenousbag by immediately adding the dissolved cangrelor to an intravenous bagcontaining saline solution in volumes such as 250 ml, 500 ml, or 1000 mlof saline solution and mixing the intravenous bag thoroughly foradministration. Cangrelor compositions should be prepared immediatelyprior to administration via infusion. It is within the skilled in theart to vary the volume of saline and amount of cangrelor in theexemplary method described above to achieve the dosage amount describedin the preferred embodiments.

The described methods can be used for patients diagnosed with symptomsof conditions such as stable or unstable angina, vascular ischemicevents, atherosclerosis, acute coronary syndrome, including STEMI orN-STEMI. The described methods can also be used for patients havingpreviously received a stent, such as a bare metal stent or adrug-eluting stent, and the treatment or prevention of stent thrombosis.

The described methods can be used for a patient before, during, andafter an invasive procedure, such as coronary artery bypass grafting,orthopedic surgeries, urological surgeries, percutaneous coronaryintervention, other general invasive procedures, such as endarterectomy,renal dialysis, cardio-pulmonary bypass, endoscopic procedures or anymedical, surgical, or dental procedure that could potentially lead toexcessive bleeding or hemorrhage.

Further, the described methods of the present invention can be used in apatient who cannot be orally administered therapies and, for whateverreason, cannot be administered long lasting thienopyridines, such asclopidogrel or Plavix®.

Results of the Methods

To determine how to administer a reversible, short-acting P2Y₁₂inhibitor or the amount of a reversible, short-acting P2Y₁₂ inhibitor tobe administered, the pharmacokinetic profile of the reversible,short-acting P2Y₁₂ inhibitor can be analyzed using the methodswell-known to a person skilled in the art.

For example, the pharmacokinetics of cangrelor has been shown to besubstantially linear, and its steady-state plasma concentrations can beachieved in less than approximately 5 minutes following theadministration of an intravenous infusion.

Cangrelor produced potent inhibition of ADP-induced platelet aggregationex vivo with half maximal inhibitory concentration (IC50) 7.72+/−1.95ng/mL. As may be seen in FIG. 1, over 80% inhibition was achieved atdoses of about 0.5 μg/kg/min and above. Inhibition by cangrelor wasrapidly reversible and platelet aggregation response restored close tobaseline within one hour of stopping the infusion. An infusion dose ofapproximately about 0.75 μg/kg/min of cangrelor can also maintainadequate antiplatelet activity during infusion in the targeted patientprior to an invasive procedure.

It has been determined that consistent and complete platelet inhibitioncan be maintained throughout cangrelor infusion with full recovery ofplatelet function within approximately one hour of infusion cessation.Clopidogrel administration at the termination of cangrelor infusion maylead to the expected degree of platelet inhibition, which may bemeasured by P-selectin expression, electrical impedance and lighttransmittance aggregometry.

Transition from PCI Dosing Regimen to Bridge Dosing Regimen, and fromBridge Dosing Regimen to PCI Dosing Regimen

An aspect of the present invention is a method of transitioning apatient from administration of cangrelor during PCI to administration ofcangrelor in preparation for surgery, or a method of transitioning apatient from administration of cangrelor in preparation for surgery toadministration of cangrelor during PCI. Another aspect of the inventionis a method of maintaining reduced platelet activity in a patient who istransitioning from administration of cangrelor during PCI toadministration of cangrelor in preparation for surgery, or who istransitioning from administration of cangrelor in preparation forsurgery to administration of cangrelor during PCI. Yet a further aspectof the invention is a method of maintaining P2Y₁₂ inhibition in apatient who is transitioning from administration of cangrelor during PCIto administration of cangrelor in preparation for surgery, or who istransitioning from administration of cangrelor in preparation forsurgery to administration of cangrelor during PCI.

The reasons why a patient may have to transition from administration ofcangrelor during PCI to administration of cangrelor in preparation forsurgery, or vice-versa, can vary. For example, as a patient isadministered cangrelor during PCI, it may be determined that surgery isnecessary due to, for instance, new information that was gathered duringPCI or complications that arose from the PCI procedure itself. On theother hand, a patient administered cangrelor during preparation forsurgery may have to undergo PCI, such as when it is discovered that thepatient is in immediate need of angioplasty or the implantation of astent. In each of these cases, the patient has to change from one dosingregimen of cangrelor to a different dosing regimen.

Transitioning from administration of cangrelor during PCI toadministration of cangrelor in preparation for surgery may be performedby administering a PCI dosing regimen, discontinuing the administrationof the PCI dosing regimen, and administering a bridge dosing regimen.Transitioning from administration of cangrelor in preparation forsurgery to administration of cangrelor during PCI may be performed byadministering a bridge dosing regimen, discontinuing the administrationof the bridge dosing regimen, and administering a PCI dosing regimen. A“PCI dosing regimen” refers to the doses of cangrelor that a patientreceives when undergoing PCI. A “bridge dosing regimen” refers to thedoses of cangrelor that a patient receives in the “bridging” periodleading up to surgery, i.e., the period of time between thediscontinuation of oral P2Y₁₂ inhibitors and surgery.

The PCI dosing regimen comprises administering intravenously acontinuous infusion of cangrelor at a rate of about 3 to about 10μg/kg/min, or about 4 μg/kg/min. The continuous infusion may beaccompanied by intravenous administration of a bolus. The bolus maycomprise about 10 to about 100 μg/kg cangrelor, such as between about 20and about 40 μg/kg cangrelor, or about 30 μg/kg cangrelor. The bolus maybe administered rapidly, for example, in less than about two minutes, orless than about one minute. Preferably, the administration of thecontinuous infusion is started immediately after the administration ofthe bolus.

The bridge dosing regimen comprises administering intravenously acontinuous infusion of cangrelor at a rate of about 0.1 to about 2μg/kg/min, or about 0.75 μg/kg/min.

The cangrelor may be administered in a pharmaceutical composition. Thepharmaceutical composition may comprise 200 μg/mL of cangrelor. Thepharmaceutical composition may also comprise sodium chloride injection0.9% U.S. Pharmacopeia (USP) or or 5% dextrose injection, USP.

In embodiments in which the patient is transitioning from administrationof cangrelor during PCI to administration of cangrelor in preparationfor surgery, the discontinuation of the administration of the PCI dosingregimen may occur at any time during the PCI continuous infusion. Theadministration of the bridge dosing regimen may occur as quickly aspossible following the discontinuation of the administration of the PCIdosing regimen. In some embodiments, the discontinuation of theadministration of the PCI dosing regimen and the administration of thebridge dosing regimen may be achieved simultaneously by lowering the PCIcontinuous infusion rate to the bridge continuous infusion rate. Theadministration of the bridge dosing regimen may be discontinued at leastabout one hour prior to administration of anesthesia for the surgery.Moreover, the administration of the bridge dosing regimen may bediscontinued after no longer than about 7 days from initiation.

In embodiments in which the patient is transitioning from administrationof cangrelor in preparation of surgery to administration of cangrelorduring PCI, the discontinuation of the administration of the bridgedosing regimen can occur any time during the bridge continuous infusion.The administration of the PCI dosing regimen may occur as quickly aspossible following the discontinuation of the administration of thebridge dosing regimen. In some embodiments, the discontinuation of theadministration of the bridge dosing regimen and the administration ofthe PCI dosing regimen may be achieved simultaneously by increasing thebridge continuous infusion rate to the PCI continuous infusion rate. Ifthe PCI dosing regimen includes the administration of a bolus, then thebolus can be administered immediately before or after the increase tothe PCI continuous infusion rate. The administration of the continuousinfusion of cangrelor in PCI dosing regimen may continue for the longerof (a) at least two hours, or (b) the duration of PCI. The continuousinfusion may be continued for a total duration of about four hours.

EXAMPLES Example 1

Without limitations, FIG. 2 provides a brief summary as to how themethods described in the present invention may be used in a patient inneed thereof. It should be understood that the method of the presentinvention is not limited to the procedure described in FIG. 2.

FIG. 2, shows a screening period 210 used for determining the dosagenecessary for achieving platelet inhibition greater than apre-determined level, for example, of approximately 60%. A pre-operativeperiod 220 of up to approximately 7 days prior to surgery can be usedfor administration of a reversible, short-acting P2Y₁₂ inhibitor. Anintra-operative period 230 lasting from the discontinuation of thereversible, short-acting P2Y₁₂ inhibitor to the end of surgery can beused.

During the screening period 210, the dosage of a reversible,short-acting P2Y₁₂ inhibitor, necessary to achieve platelet inhibitiongreater than approximately 60% can be determined. Other suitable levelsof percent inhibition are approximately 65, 70, 75, 80, 85, 90, 95 and100%. For example, intravenous infusion of a reversible, short-actingP2Y₁₂ inhibitor can be administered to a patient in doses typicallyranging from about 0.5 μg/kg/min to about 5.0 μg/kg/min, preferablyabout 0.5 μg/kg/min to about 2.0 μg/kg/min and particularly at doses of0.5 μg/kg/min, 0.75 μg/kg/min, 1.0 μg/kg/min, 1.5 μg/kg/min and 2.0μg/kg/min, until measured platelet inhibition is greater than thepre-determined level. Smaller or larger doses may also be used as neededto achieve the required level of platelet inhibition.

Optionally, the dosage of a reversible, short-acting P2Y₁₂ inhibitor forany particular patient can also be determined ahead of time, so as toreduce the need to give multiple doses to achieve the required level ofplatelet inhibition. In all instances where measurement of plateletinhibition is needed, a baseline value should be obtained to accuratelydetermine when acceptable levels have been reached.

During pre-operative period 220, administration of a reversible,short-acting P2Y₁₂ inhibitor can be initiated the day the decision ismade to discontinue the long-acting irreversible platelet inhibitor andmay be continued throughout pre-operative period 220. In anotherembodiment, administration of cangrelor can be made within 3 days ofceasing administration of the long-acting irreversible plateletinhibitor.

A patient can undergo CABG within 3 days of ceasing administration ofthe long-acting irreversible platelet inhibitor. The dose of such areversible, short-acting P2Y₁₂ inhibitor can remain constant or can beperiodic during the treatment period. Preferably the dosage of cangrelorremains continuous during the treatment period of about 2 to about 7days. Treatment with reversible, short-acting P2Y₁₂ inhibitor may thenbe terminated from about one hour to about 6 hours before an invasiveprocedure.

Also during pre-operative period 220, any number of procedures and/ortests can be performed in conjunction with the present invention, suchas hemoglobin, hematocrit, white blood cells, and platelet counttesting; serum creatinine testing; measurement of inhibition of plateletactivation; and assessment of concomitant medications, adverse events,serious adverse events and other various clinical endpoints.Additionally, procedures such as creatine kinase (CK) and creatinekinase with muscle- and brain-type subunits (CK-MB) and VerifyNow® P2Y12assays, for example, can be performed within 24 hours prior to surgery.

During intra-operative period 230, administration of a reversible,short-acting P2Y₁₂ inhibitor can be stopped between from about at least1 hour and up to approximately 3 hours prior to administration ofanesthesia for surgery. Basic standard of care treatment is used for thesurgical period as understood by those having skill in the art.Collection of concomitant medications and assessments of adverse events,serious adverse events and clinical endpoints can also be performedduring this period as needed.

Example 2

FIG. 3 describes a non-limiting exemplary method for maintaining orreducing platelet activity in patients who were previously treated withthienopyridine prior to undergoing an invasive procedure such as CABG.

In FIG. 3, a total of 207 patients were studied. Patients were includedin this study if they met all of the following criteria: (1) Must be atleast 18 years of age; (2) Anticipate non-emergent CABG surgery, either“on-pump” or “off-pump,” no sooner than 48 hours from randomization butno longer than 7 days from randomization, with patient to remainhospitalized until planned CABG; and (3) Have received a thienopyridine(at least 75 mg of clopidogrel, 500 mg ticlopidine, or 10 mg prasugrel)within 72 hours prior to enrollment in the study for either thetreatment of an acute coronary syndrome, regardless of time from ACS,and/or as long-term preventative therapy following drug-eluting or baremetal stent treatment.

Patients were excluded from the study if any of the following exclusioncriteria applied prior to randomization: (1) Confirmed or suspectedpregnancy (if woman of child-bearing potential) or lactating females;(2) Cerebrovascular accident within one year; (3) Intracranial neoplasmor history of intracranial surgery; (4) History of bleeding diathesis;(5) Thrombocytopenia (platelet count of less than 100,000/μL); (6) KnownInternational Normalized Ratio (INR) greater than 1.5 at screening.; (7)Requirement for dialysis treatment (hemodialysis or peritoneal); (8)Estimated Glomeular filtration rate eGFR <30 ml/min; (9) Administrationof abciximab within 24 hours of randomization or administration ofeptifibitide or tirofiban within 12 hours of randomization.; (10) Plansto continue oral anticoagulant, thienopyridine or GPIIb/IIIa antagonisttherapy in the pre-operative period.; (11) Known or suspectedcoagulopathy; (12) Refusal to receive blood transfusion; (13) Receipt offibrinolytic therapy in the 12 hours preceding randomization; (14)Allergy, hypersensitivity, or contraindication to cangrelor, mannitol,sorbitol, or microcrystalline cellulose; (15) High likelihood of beingunavailable for follow-up; (16) Participation in other studies involvingthe evaluation of other investigational drugs or devices within 30 daysof randomization; or (17) Any disease or condition which, in thejudgment of the health care provider, would place the patient at unduerisk by participating in the study.

Patients were randomized into two groups, a cangrelor plus standard ofcare (SOC) group, and a placebo plus SOC group. A dose study wasperformed, for cangrelor plus SOC and placebo plus SOC respectively. Adose of 0.75 μg/kg/min was confirmed for the cangrelor plus SOC andplacebo plus SOC groups.

In the placebo plus SOC group, patients received only SOC, in which thethienopyridine is discontinued after the need for surgery had beendetermined and a placebo infusion is administered. In the cangrelor plusSOC group, a cangrelor infusion was started in addition to SOC when thethienopyridine was discontinued after the need for surgery had beendetermined. The infusions (cangrelor or matching placebo) were continuedthroughout the pre-operative period. Patients can wait 5 days afterdiscontinuation of clopidogrel before undergoing surgery but the timingof surgery can vary and be left to the discretion of the health carepractitioner with a maximum of 7 days of cangrelor infusion.

Daily measurements of platelet inhibition were taken using theVerifyNow® P2Y12 assay system.

All patients randomized receive SOC and waited up to five days afterdiscontinuation of thienopyridine before undergoing CABG. Antiplatelettherapy with aspirin was maintained during this time. Anti-thromboticssuch as unfractionated heparin and enoxaparin were allowed and given atthe discretion of the health care provider. It was recommended thatenoxaparin be discontinued >24 hours before CABG although concomitantuse of other antiplatelet and anti-thrombic agents is contemplated bythe invention described here. It was recognized that clinical events mayoccur leading to surgery before the 5 day waiting period is completedand therefore the decision to proceed to surgery was left to thediscretion of the health care provider.

For patients randomized to the cangrelor arm, cangrelor infusion wasstarted as quickly as possible and no more than 6 hours afterrandomization. Patients received an infusion of cangrelor, in additionto their SOC therapy, at a rate of 0.75 μg/kg/min.

Cangrelor was infused continuously via a dedicated peripheral or centralline for at least about 2 days and up to about 7 days. The dose ofcangrelor remained constant during the infusion period. The cangrelorinfusion was terminated at least one and no more than six hours beforeinduction of anesthesia for the scheduled CABG surgery. Induction ofanesthesia is defined as the start time of IV anesthesia. Patients wereinfused with cangrelor for a minimum of 48 hours prior to termination.

Patients not randomized to receive cangrelor received a placebo infusionadministered in the same manner as the cangrelor infusion in addition totheir SOC therapy.

FIGS. 4-1 and 4-2 include a table that summarizes the study assessmentsby time point. This study consisted of 5 periods: (1)Screening/Randomization Period, (2) Pre-operative (Days 1-7 defined asthe period from randomization to discontinuation of cangrelor), (3)Intra-operative (from discontinuation of cangrelor to end of CABGsurgery), (4) Post-operative Follow-up (from end of CABG surgery tohospital discharge), and (5) 30-Day Follow-up (30+ 5 days from time ofCABG).

Pre-operative Period (Randomization until discontinuation of cangrelor):Just prior to the administration of cangrelor, a VerifyNow® P2Y12 Assaywas performed to obtain a baseline assessment. Testing was performedirrespective of the timing of last dose of thienopyridine received.Immediately following the VerifyNow® P2Y12 Assay, the cangrelorcomposition was prepared and an infusion at the rate of 0.75 μg/kg/minwas started. This infusion was maintained until 1 to 6 hours prior toanesthesia administration for the CABG surgery. The following tests wereperformed daily, at approximately the same time, during all days ofcangrelor infusion: Hematology labs [hemoglobin, hematocrit, white bloodcells (WBC), and platelet count] PRU and percent platelet inhibitiondetermined by VerifyNow® P2Y12 Assay Assessment of concomitantmedications. Within 12 hours prior to surgery, the following procedureswere conducted: Additional VerifyNow® P2Y12 assay just prior tocangrelor termination. If the last on-infusion VerifyNow® sample waswithin 12 hours of cangrelor discontinuation, an additional draw was notrequired prior to termination of cangrelor.

Table 1 below represents the results of cangrelor and placebo treatmentduring the pre-operative period.

TABLE 1 Summary of PRU by Day Cangrelor Placebo Stat (N = 93) (N = 90)Screening: Patients w/PRU <240 n/N (%) 53/85 (62.4) 45/86 (52.3) PRU N85   86  MEAN ± SD 210.9 ± 94.0  214.1 ± 85.9 MEDIAN 201.0  233.5 (Q1,Q3) 166, 280  151, 279 (MIN, MAX) 3, 418  10, 395 Day 1 sample Patientsw/PRU <240 n/N (%) 80/80 (100)  34/76 (44.7) PRU N 80   76  MEAN ± SD45.5 ± 47.1 232.7 ± 74.2 MEDIAN 31.0 249.0 (Q1, Q3) 5, 78  178, 287(MIN, MAX) 0, 169  47, 367 Day 2 sample: Patients w/PRU <240 n/N (%)69/70 (98.6) 25/73 (34.2) PRU N 70   73  MEAN ± SD 58.8 ± 58.1 239.2 ±71.1 MEDIAN 40.0 256.0 (Q1, Q3) 6, 100 218, 282 (MIN, MAX) 0, 271  64,354 Day 3 sample: Patients w/PRU <240 n/N (%) 55/55 (100)  21/57 (36.8)PRU N 55   57  MEAN ± SD 69.2 ± 59.8 250.4 ± 64.7 MEDIAN 52.0 263.0 (Q1,Q3) 8, 117 200, 306 (MIN, MAX) 0, 229 105, 358 Day 4 sample: Patientsw/PRU <240 n/N (%) 33/33 (100)   7/34 (20.6) PRU N 33   34  MEAN ± SD80.3 ± 61.7 286.5 ± 65.5 MEDIAN 78.0 296.0 (Q1, Q3) 33, 115  241, 344(MIN, MAX) 1, 219 118, 406 Day 5 sample: Patients w/PRU <240 n/N (%) 7/7 (100)  6/24 (25.0) PRU N 7  24  MEAN ± SD 52.1 ± 58.1 284.0 ± 64.0MEDIAN 30.0 285.5 (Q1, Q3) 9, 117 244, 328 (MIN, MAX) 7, 151 140, 388Day 6 sample: Patients w/PRU <240 n/N (%)  6/6 (100)  3/14 (21.4) PRU N6  14  MEAN ± SD 62.7 ± 74.7 291.3 ± 54.1 MEDIAN 45.5 280.0 (Q1, Q3) 9,67  250, 329 (MIN, MAX) 3, 206 217, 399 Day 7 sample: Patients w/PRU<240 n/N (%)  1/1 (100)  0/2 (0.0) PRU N 1  2   MEAN ± SD 3.0 ± .  343.5± 4.9  MEDIAN  3.0 343.5 (Q1, Q3) 3, 3  340, 347 (MIN, MAX) 3, 3  340,347 Last on-treatment sample: Patients w/PRU <240 n/N (%) 83/84 (98.8)26/84 (31.0) PRU N 84   84  MEAN ± SD 68.9 ± 67.8 263.7 ± 68.3 MEDIAN53.0 263.5 (Q1, Q3) 8, 110 227, 311 (MIN, MAX) 0, 271  81, 399 Lastpost-treatment pre-CABG: Patients w/PRU <240 n/N (%) 21/78 (26.9) 15/75(20.0) PRU N 78   75  MEAN ± SD 279.7 ± 106.5 297.8 ± 67.3 MEDIAN 293.0 299.0 (Q1, Q3) 228, 357  256, 345 (MIN, MAX) 1, 471 144, 445

The data in Table 1 indicates that infusion of Cangrelor at a dose of0.75 μg/kg/min between day 1 to day 7 maintains PRU values below 240 inover 90% of the patients studied. The table further indicates that forthe “last post-treatment pre-CABG” where cangrelor infusion isterminated but prior to CABG, the level of PRU has resumed to levelsprior to cangrelor treatment.

Intra-operative Period (Period from discontinuation of cangrelor untilend of CABG surgery): The Intra-operative period started at terminationof cangrelor infusion (surgery start is defined as time of firstincision). Cangrelor infusion was stopped at least 1 hour and a maximumof 6 hours prior to administration of anesthesia for surgery. Standardof care treatment was used for the surgical period. Collection of thefollowing assessments were conducted during this period: (i) serumcreatinine and liver function tests (LFTs)—following discontinuation ofcangrelor but prior to surgery (surgery start time is defined as thetime of first surgical incision); (ii) VerifyNow® P2Y12 assay just priorto first surgical incision; and (iii) concomitant medications andassessments of adverse events, serious adverse events and clinicalendpoints.

In the case of administering and ceasing the therapy prior to surgery inaccordance with one embodiment of the present invention, such use allowspatients to undergo surgery or other invasive procedures withoutexcessive perioperative bleeding.

Table 2 represents the bleeding risks associated with cangrelor andplacebo treatment.

TABLE 2 Summary of CABG Related Bleeding During the CABP Procedurethrough Hospital Discharge Cangrelor Placebo Stat (N = 106) (N = 101)CABG related bleeding n/N (%) 10/102 (9.8)  10/96 (10.4) Fatal bleedingn/N (%) 0 0 Periop. intracranial n/N (%) 0 0 bleeding Re operation forn/N (%) 2/102 (2.0) 2/96 (2.1) bleeding Whole Blood or n/N (%) 7/102(6.9) 8/96 (8.3) pRBC Transfusion >= 5 units 24 hour CT output >= 2 Ln/N (%) 3/102 (2.9) 4/96 (4.2) CT denotes computed tomography.

The results of Table 2 indicates that bleeding risk associated withcangrelor treatment is the same as or similar to treatment with placebo.

Table 3 represents the overall incidence of ischemic events

TABLE 3 Overall Incidence of Ischemic Events Cangrelor Placebo Stat (N =106) (N = 101) Pre-procedure Death/MI/IDR/Stroke n/N (%) 3/106 (2.8)4/101 (4.0) Death n/N (%) 1/106 (0.9) 3/101 (3.0) MI n/N (%) 2/106 (1.9)0/101 (0.0) IDR n/N (%) 1/106 (0.9) 0/101 (0.0) Stroke n/N (%) 0/106(0.0) 1/101 (1.0) Post-procedure Death/MI/IDR/Stroke n/N (%) 4/102 (3.9)4/96 (4.2) Death n/N (%) 1/102 (1.0) 2/96 (2.1) MI n/N (%) 2/102 (2.0)1/96 (1.0) IDR n/N (%) 2/102 (2.0) 0/96 (0.0) Stroke n/N (%) 1/102 (1.0)1/96 (1.0) Pre and Post-procedures Death/MI/IDR/Stroke n/N (%) 10/106(9.4)  8/101 (7.9) Death n/N (%) 2/106 (1.9) 5/101 (5.0) MI n/N (%)4/106 (3.8) 1/101 (1.0) IDR n/N (%) 6/106 (5.7) 0/101 (0.0) Stroke n/N(%) 1/106 (0.9) 2/101 (2.0) MI denotes myocardial infarction. IDRdenotes ischemia drive revascularization.

The results of Table 3 indicate that the ischemic events relating to themethods described herein with the use of cangrelor are comparable to theplacebo.

Post-operative Period (Period from end of CABG surgery to hospitaldischarge): The following procedures were performed following surgery(end of CABG surgery is defined as the placement of the last suture):VerifyNow® P2Y12 Assay was performed within 1 hour following surgeryHematology labs, 12 lead-ECG and VerifyNow® P2Y12 Assay were performed24-hours (±1 h) following surgery. Chest tube output will be assessed at4 hours (±1 h) and 24 hours (±1 h) following surgery.

Example 3

In another example and in accordance with one embodiment of the presentinvention, the administration of the at least one reversible,short-acting P2Y₁₂ inhibitor occurs during an invasive procedure beingperformed on the subject. In this manner, it is contemplated that theadministration of the inhibitor would occur intravenously as the subjectcannot take the therapy orally.

Example 4a

In another example and in accordance with another embodiment of thepresent invention, the administration of the at least one reversible,short-acting P2Y₁₂ inhibitor occurs after an invasive procedure has beenperformed on the subject. The administration of the inhibitor in thepost surgery scenario can occur in a variety of methods as describedabove. It is contemplated that the administration of the inhibitor mayalso occur intravenously post surgery if the subject cannot take thetherapy orally, for example, if the subject is comatose.

Example 4b The Study for Using Cangrelor in Early Post-Operative Period

Current standard of care for antiplatelet maintenance therapy after PCIin patients with implanted stents is based on recommendations of theACC/AHA guidelines (Fleisher L A, et al., ACC/AHA 2007 guidelines onperioperative cardiovascular evaluation and care for noncardiac surgery:a report of the ACC/AHA Task Force on Practice Guidelines. Circulation.2007 Oct. 23; 116(17): e418-99) that suggest an early initiation of dualantiplatelet therapy and continuation of maintenance therapy withaspirin and clopidogrel after PCI from 6 to 12 months, depending on thestent type, in order to prevent post-procedural stent thrombosis. Bothaspirin and clopidogrel are irreversible platelet antagonists, thereforeACC/AHA guidelines recommend cessation of clopidogrel beforenon-emergent surgical procedures in order to minimize bleeding risks.

However, should patients with implanted stents require a surgicalprocedure, early cessation of clopidogrel would increase the risk forischemic events and stent thrombosis (Berger et al., Circulation. 2002Oct. 22; 106(17): 2284-7; Ho et al. JAMA. 2008 Feb. 6; 299(5): 532-9).Conversely, maintaining irreversible platelet inhibition with aspirinand clopidogrel leads to unacceptable operative bleeding risk (Fox etal., Circulation. 2004; 110: 1202-1208; Shim et al., J Thorac CardiovascSurg. 2007 July; 134(1): 59-64; Pickard et al., Pharmacotherapy. 2008March; 28(3): 376-92. Review).

Because of the risk of bleeding from the surgical sites, surgeons preferto avoid using anticoagulant agents in early post-operative periodespecially with irreversible oral therapy that will not allow predictingthe level of platelet inhibition and fast recovery of platelet functionwhen surgical procedure could be associated with high risk ofpost-operative bleeding.

It is well known that surgical interventions trigger platelet activationand aggregation, hence increasing the risk of stent thrombosis inpost-operative period if patient do not continue antiplatelet therapy.

It has been demonstrated in several studies that early initiation ofanticoagulant therapy may diminish the risk of venous thrombosis (SegersA. J Thromb Haemost. 2008 August; 6(8): 1313-8; Turpie et al., Lancet.2009 May 1), however there is no consensus or standard antiplatelettherapy regimen designed to reduce the risk of arterial stent thrombosisin patients with implanted stents requiring surgical procedures.

Typically, at conclusion of surgical procedure a complete hemostasis isachieved, however, the risk of bleeding from the surgical site remainshigh during the first post-operative hours. Initiation of antiplatelettherapy during the immediate-early period after surgery may furtherincrease that risk. Conversely, a delay of continuation of antiplateletmaintenance therapy will significantly increase the risk of stentthrombosis, considering that surgical procedure triggers plateletactivation and aggregation. Therefore, an early therapy with reversibleantiplatelet agent that could be titrated to a desirable level ofplatelet inhibition and have ultra-short platelet function recovery timecould be beneficial in preventing stent thrombosis in that category ofpatients. Moreover, this type of agent will be safe because it may allowcomplete recovery of platelet function after discontinuation in case ofbleeding.

Cangrelor is a potent, reversible and specific P2Y₁₂ receptor antagonistthat would allow overcoming the limitations of currently used dualantiplatelet therapy with aspirin and clopidogrel thanks to its rapidonset and offset of action with steady-state plasma concentrations thatcan be achieved within minutes and titrated to modulate the level ofplatelet inhibition and most importantly, it is rapidly metabolized withan short half-life, allowing complete recovery of platelet function inless than 60 min. Therefore, cangrelor could be an ideal antiplateletagent for managing platelet inhibition in early post-operative period inpatients with implanted stents requiring a surgical procedure.

The optimal platelet inhibitory dose and regimen for cangrelor infusionin post-operative period and transitioning to oral antiplatelet therapycan be determined.

The patient population can be ACS patients with implanted stents afterPCI who require a major surgical procedure (CABG, gastrointestinal (GI)anastomoses, pulmonary resection, prostatectomy, orthopedic procedures,etc.), N=40 subjects (4 groups with 10 subjects in each group).Cangrelor infusion will be initiated 1-2 hours after completion ofsurgical procedure at surgeons' discretion. The subjects will berandomized into the following groups:

Group 1: Cangrelor 0.5 μg/kg/min dose infusion for 24 hrs transitioningto oral antiplatelet therapy with 300 mg of clopidogrel loading doseafter infusion discontinuation followed by 75 mg daily maintenance dosethereafter;

Group 2: Cangrelor 0.5 μg/kg/min infusion for 24 hrs transitioning tooral antiplatelet therapy with 600 mg of clopidogrel loading dose afterinfusion discontinuation followed by 75 mg daily maintenance dosethereafter;

Group 3: Cangrelor 1 μg/kg/min infusion for 24 hrs transitioning to oralantiplatelet therapy after infusion discontinuation transitioning tooral antiplatelet therapy with 300 mg of clopidogrel loading dose afterinfusion discontinuation followed by 75 mg daily maintenance dosethereafter;

Group 4: Cangrelor 1 μg/kg/min infusion for 24 hrs transitioning to oralantiplatelet therapy after infusion discontinuation transitioning tooral antiplatelet therapy with 600 mg of clopidogrel loading dose afterinfusion discontinuation followed by 75 mg daily maintenance dosethereafter.

The primary endpoints will be: (1) acute sent thrombosis during the 48hrs after the surgical procedure, and (2) major and minor bleedingsduring the 48 hrs after the surgical procedure.

The methods of evaluation will be: (1) platelet aggregation usingVerifyNow® P2Y12 test, (2) hemodynamic measurements, (3) blood tests,(4) clinical observations for minor capillary bleeding signs (petechiae,hematoma), (5) Diagnostic imaging of intracranial, peritoneal andpleural cavities using computed tomography (CT), magnetic resonanceimaging (MRI), ultrasound (US), when necessary to detect potentialbleeding complications (blood accumulation).

Example 5 Population Pharmacodynamic Evaluation of Cangrelor

Objective: The objective of this evaluation was to develop a populationpharmacodynamic model to describe the concentration effect relationshipbetween cangrelor exposure and the marker of platelet aggregation,namely PRU, as measured by VerifyNow®, Accumetrics in order to, amongother things, determine how best to transition from the bridge dose tothe PCI dose, and vice versa.

Data and Database Creation: The database created for this evaluationincluded a total of 1102 PRU observations from 220 bridge and PCIpatients. A summary of the demographics is provided in Table 4. Thesepatients were generally older and heavier than volunteers.

TABLE 4 Summary of Demographics of the Patients Involved in the Study.Covariate (units) Mean Median SD Max Min Age (yrs) 63 62 11 92 36 Weight(kg) 86.8 85.4 16 154 52 BMI (kg/m2) 29.5 29.1 5.07 50.1 19.4 Sex MaleFemale Number 151 59 Study CHAMPION PCI/Platform (PCI) Platelet SubstudyBridge Number 104 116 Patient type PCI ACS Stent Number 54 69 97Treatment Group PCI/substudy 30 Cohort 1: Cohort 1: Cohort 2: μg/kgbolus + 0.5 μg/ 0.75 μg/ 75 μg/ 4 μg/kg/min infusion kg/min kg/minkg/min Number 104 5 6 105 ACS denotes acute coronary syndrome. PCIdenotes percutaneous coronary intervention.

Simulation Assessments: In order to address the pharmacodynamicobjectives and show how best to transition from one dose to the otherdose (i.e., Bridge and PCI), stochastic simulation was performed inNONMEM®. A PRU value of 208 was chosen throughout the evaluation as thecutoff to evaluate the effectiveness of varying doses of cangrelor indifferent patient types. The results were evaluated graphically bygenerating 95% confidence intervals and by summarizing the percentage ofpatients expected to achieve a PRU value of 208 or less. For eachsimulation scenario, 1000 patients were simulated using covariates drawnfrom the original distribution of covariate values. Parameter precisionwas not taken into account for these simulations.

Patients from the bridge subset of data were sampled. At varying timesafter initiation of the bridge dose, the patient type was switched tothe PCI type (to reflect reduced sensitivity to cangrelor) and the dosewas increased to the PCI dose. The percentage of subjects achieving thedesired PRU result of 208 or lower were tabulated. For completeness, thereverse transition (from PCI to bridge) was also simulated, and resultstabulated.

Description of PRU Pharmacodynamic Model: The PRU pharmacodynamic modelwas a direct effect sigmoidal inhibitory model with terms describing thebetween subject variability included on the drug effect parameter (Emax)and baseline. An additive residual error was used. The modelincorporated a slowly increasing baseline in bridge patients(attributable to the effect of previous dosing with clopidogrel wearingoff) and a slowly decreasing baseline in PCI patients (owing to thethrombotic stimulus of the stenting/PCI gradually lessening after theprocedure together with onset of effect of other post proceduretreatments). The model also included a covariate for patient type ondrug effect and the effects of age and sex on baseline. The equationsfor the final PRU pharmacodynamic model are provided below.

${BaselinePRU} = {\theta_{6}*\left( {1 - {{sex}*\theta_{11}}} \right)*\left( \frac{Age}{30} \right)^{\theta_{12}}*{\exp\left( {\eta\; 5} \right)}}$EFF = θ₇ * (1 − patient  type * θ₁₀) * exp (η4) IC 50 = θ₈ γ = θ₉if  (Study = 1)wearoff = θ₁₃  else   θ₁₄${DrugEffect} = \frac{{Eff}*{Cp}^{\gamma}}{{{IC}\; 50^{\gamma}} + {Cp}^{\gamma}}$PRU = BaselinePRU − DrugEffect − wearoff * Time(hrs)

The parameters were estimated with good precision with the exception ofthe age effect on baseline. All other diagnostics and model evaluationssuggested that the model performance was acceptable. The parameters fromthe model are provided in Table 5.

TABLE 5 Parameter estimates for base PRU pharmacodynamic model. BetweenParameter Population SE Subject SE (Units) Mean (CV %) Variability (CV%) Baseline 215 7 23.22 15 Wear off PCI (l/h) −3.15 13.7 Wear off bridge(l/h) 0.838 7.3 Age effect 0.228 39.7 Gender effect −0.162 25.3 DrugEffect 148 6.2 19.21 31.7 PCI patient effect −0.624 17 IC50 0.0717 35.4NE NE Gamma 1.71 21 NE NE Additive Residual Error 62.6 2.7 NE - notestimated.

Several covariates were identified in this evaluation. There was aneffect of gender on the baseline PRU, with females having a 16% higherbaseline PRU than males. Age was also found to be important on thebaseline PRU value. The impact of age is provided in Table 6.

TABLE 6 Effect of age on baseline PRU. Age (yrs) Baseline PRU Percent ofReference 30 215 100 40 230 107 50 242 112 60 252 117 70 261 121 80 269125

Over the age range from 30 to 80 years, the baseline PRU would beexpected to increase by 25%. There was a larger impact of patient type(i.e., PCI patient versus bridge patient) on the drug effect which isshown in FIG. 5. This impact is a 62% decreased effect in PCI relativeto bridge and shows why the percentage of simulated PCI patientsachieving the threshold response of 208 is somewhat lower than seen inthe bridge patients.

Simulation Results—Evaluation of the Probability of Achieving theDesired PRU Cutoff: The probability of the PCI and bridge patientsachieving the desired PRU cutoff value of 208 is provided for theoverall indication in Table 7.

TABLE 7 Probability of achieving desired PRU result by patient type -overall findings. Study Patient Type Dose Probability 1 PCI 30 μg/kgbolus with 4 μg/kg/min 0.827462 2 Bridge 0.75 μg/kg/min 0.961949

As can be seen, despite the lower dose used for the bridge patients, theprobability of achieving the threshold is higher in these patients thanthe PCI patients because the PCI patients had a higher immediatethrombotic stimulus.

Similarly the probability of maintaining the PRU below the thresholdafter stratification of patients by weight over the range of weights inthe database showed no overall trends (Table 8), suggesting that thedrug concentration is sufficient to provide approximately 80% at orbelow threshold for PCI patients and over 90% at or below threshold PRUfor bridge patients with the suggested dose.

TABLE 8 Probability of achieving desired PRU result by patient type andweight. Weight Patient Range Proba- Study Type Dose (kg) bility 1 PCI 30μg/kg bolus with 4 μg/kg/min (50, 80) 0.839885 1 PCI 30 μg/kg bolus with4 μg/kg/min (80, 90) 0.795222 1 PCI 30 μg/kg bolus with 4 μg/kg/min (90, 100) 0.7975 1 PCI 30 μg/kg bolus with 4 μg/kg/min (100, 120)0.87275 1 PCI 30 μg/kg bolus with 4 μg/kg/min (120, 160) 0.856 2 Bridge0.75 μg/kg/min (50, 80) 0.95797 2 Bridge 0.75 μg/kg/min (80, 90) 0.980042 Bridge 0.75 μg/kg/min  (90, 100) 0.952081 2 Bridge 0.75 μg/kg/min(100, 120) 0.957313 2 Bridge 0.75 μg/kg/min (120, 160) 0.9915

There was no marked trend in the probability of patients achieving thethreshold with age (Table 9).

TABLE 9 Probability of achieving desired PRU result by patient type andage. Age Patient Range Proba- Study Type Dose (yrs) bility 1 PCI 30μg/kg bolus with 4 μg/kg/min (30, 50) 0.896722 1 PCI 30 μg/kg bolus with4 μg/kg/min (50, 60) 0.806719 1 PCI 30 μg/kg bolus with 4 μg/kg/min (60,70) 0.836735 1 PCI 30 μg/kg bolus with 4 μg/kg/min (70, 80) 0.778786 1PCI 30 μg/kg bolus with 4 μg/kg/min  (80, 100) 0.791333 2 Bridge 0.75μg/kg/min (30, 50) 0.994444 2 Bridge 0.75 μg/kg/min (50, 60) 0.98919 2Bridge 0.75 μg/kg/min (60, 70) 0.984217 2 Bridge 0.75 μg/kg/min (70, 80)0.93135 2 Bridge 0.75 μg/kg/min  (80, 100) 0.869444

There was no marked trend in the probability of patients achieving thethreshold with gender (Table 10).

TABLE 10 Probability of achieving desired PRU result by patient type andsex. Patient Study Type Dose Sex probability 1 PCI 30 μg/kg bolus with 4μg/kg/min Male 0.866044 1 PCI 30 μg/kg bolus with 4 μg/kg/min Female0.754583 2 Bridge 0.75 μg/kg/min Male 0.982444 2 Bridge 0.75 μg/kg/minFemale 0.901222

These results support the selection of a higher dose for PCI patientsthan for Bridge patients and suggest that there should be no need toadjust dose for age or gender.

Transition from Bridge to PCI: The results of the simulated transitionfrom the bridge setting (0.75 μg/kg/min) to the PCI setting (4μg/kg/min) with and without the administration of an IV bolus loadingdose for PCI (30 μg/kg) are provided for a reference male patient inFIG. 6 and FIG. 7, respectively. As was seen with the evaluation ofprobability of achieving the threshold PRU response, the probability isgenerally lower for the PCI than bridge patient in all settings. Thesame scenarios were simulated in a reference female patient with andwithout the IV bolus dose (FIG. 8 and FIG. 9, respectively). The benefitof adding a bolus dose when transitioning from bridge to PCI is somewhatlimited, but the probability of maintaining the PRU value below 208 ishigher with the recommended loading dose than without such IV bolus doseprior to PCI.

Transition from PCI to Bridge: The results of the stochastic simulationsfrom the PCI setting (30 μg/kg bolus with 4 μg/kg/min) to the bridgesetting (0.75 μg/kg/min) are provided for the same virtual male andfemale patient in FIG. 10 and FIG. 11, respectively. In thesesimulations, patients received the recommended PCI dose for 2 hours,then were transitioned directly to the recommended bridge dose for 8hours. PRU samples were taken hourly. Because these virtual patientswere simulated to reflect a PCI patient (and who would not thereforehave had a high dose of cangrelor prior to PCI), the wearing off effectseen with the bridge study was turned off. However the ability of asubject to respond to cangrelor was changed once bridge dosing wasinitiated.

Although these figures suggest a substantial difference between malesand females, the determined probability of achieving a PRU below thethreshold of 208 was similar. Thus these figures reflect the inherentvariability of the PRU assay more than any difference in inherentresponsiveness to treatment.

The results of the stochastic simulations suggest that whentransitioning from the bridge setting to the PCI setting, or vice versa,there is no need to modify the cangrelor dosing (e.g., dose titration)from that which is routinely used for these indications. PCI patientsbeing transitioned to surgery can be switched from 4 μg/kg/min cangrelordirectly to 0.75 μg/kg/min cangrelor. Surgical patients beingtransitioned to PCI can be switched directly from 0.75 μg/kg/mincangrelor to 4 μg/kg/min cangrelor, either with or without the 30 μg/kgbolus cangrelor dose.

Those of ordinary skill in the art will recognize that manymodifications and variations of the present invention may be implementedwithout departing from the spirit or scope of the invention. Thus, it isintended that the present invention cover the modification andvariations of this invention provided they come within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A method of maintaining platelet P2Y₁₂ receptorinhibition in a patient in need thereof who is being treated with along-acting irreversible P2Y₁₂ inhibitor and is in need of an invasiveprocedure, the method comprising: (a) discontinuing the treatment withthe long-acting irreversible P2Y₁₂ inhibitor; (b) administeringintravenously a 0.75 μg/kg/min continuous infusion of cangrelor; and (c)discontinuing the administration of cangrelor at least about one hourprior to administration of anesthesia for the invasive procedure.
 2. Themethod of claim 1, wherein prior to the administration of cangrelor thepatient is at an increased risk for thrombotic events when treatmentwith the long-acting irreversible P2Y₁₂ inhibitor is discontinued. 3.The method of claim 1, wherein the invasive procedure is a surgicalprocedure.
 4. The method of claim 1, wherein the cangrelor isadministered as quickly as possible following the discontinuation oftreatment with the long-acting irreversible P2Y₁₂ inhibitor.
 5. Themethod of claim 1, wherein the long-acting irreversible P2Y₁₂ inhibitoris in an oral dosage form.
 6. The method of claim 5, wherein thelong-acting irreversible P2Y₁₂ inhibitor is a thienopyridine.
 7. Themethod of claim 6, wherein the cangrelor is administered within about 5days of the discontinuation of treatment with the thienopyridine.
 8. Themethod of claim 6, wherein the administration of cangrelor isdiscontinued after no longer than about 7 days from initiation of theadministration of cangrelor.
 9. The method of claim 1, wherein thepatient has acute coronary syndrome (ACS).
 10. The method of claim 1,wherein the patient previously received a stent.
 11. The method of claim6, wherein the thienopyridine is selected from a group consisting ofclopidogrel, ticlopidine, prasugrel, and a combination thereof.
 12. Amethod of maintaining platelet P2Y₁₂ receptor inhibition in a patient inneed thereof who has acute coronary syndrome (ACS), is being treatedwith a long-acting irreversible P2Y₁₂ inhibitor, and is at an increasedrisk for thrombotic events when said treatment is discontinued due tothe need for a surgical procedure, the method comprising: (a)discontinuing the treatment with the long-acting irreversible P2Y₁₂inhibitor; (b) administering intravenously a 0.75 μg/kg/min continuousinfusion of cangrelor; and (c) discontinuing the administration ofcangrelor at least about one hour prior to administration of anesthesiafor the surgical procedure.
 13. The method of claim 12, wherein thecangrelor is administered as quickly as possible following thediscontinuation of treatment with the long-acting irreversible P2Y₁₂inhibitor.
 14. The method of claim 12, wherein the long-actingirreversible P2Y₁₂ inhibitor is in an oral dosage form.
 15. The methodof claim 14, wherein the long-acting irreversible P2Y₁₂ inhibitor is athienopyridine.
 16. The method of claim 15, wherein the cangrelor isadministered within about 5 days of the discontinuation of treatmentwith the thienopyridine.
 17. The method of claim 15, wherein theadministration of cangrelor is discontinued after no longer than about 7days from initiation of the administration of cangrelor.
 18. The methodof claim 15, wherein the thienopyridine is selected from a groupconsisting of clopidogrel, ticlopidine, prasugrel, and a combinationthereof.
 19. A method of maintaining platelet P2Y₁₂ receptor inhibitionin a patient in need thereof who previously received a stent, is beingtreated with a long-acting irreversible P2Y₁₂ inhibitor, and is at anincreased risk for thrombotic events when said treatment is discontinueddue to the need for a surgical procedure, the method comprising: (a)discontinuing the treatment with the long-acting irreversible P2Y₁₂inhibitor; (b) administering intravenously a 0.75 μg/kg/min continuousinfusion comprising cangrelor; and (c) discontinuing the administrationof cangrelor at least about one hour prior to administration ofanesthesia for the surgical procedure.
 20. The method of claim 19,wherein the cangrelor is administered as quickly as possible followingthe discontinuation of treatment with the long-acting irreversible P2Y₁₂inhibitor.
 21. The method of claim 19, wherein the long-actingirreversible P2Y₁₂ inhibitor is in an oral dosage form.
 22. The methodof claim 21, wherein the long-lasting irreversible P2Y₁₂ inhibitor is athienopyridine.
 23. The method of claim 22, wherein the cangrelor isadministered within about 5 days of the discontinuation of treatmentwith the thienopyridine.
 24. The method of claim 22, whereinadministration of the cangrelor is discontinued after no longer thanabout 7 days from initiation of administration of the cangrelor.
 25. Themethod of claim 22, wherein the thienopyridine is selected from a groupconsisting of clopidogrel, ticlopidine, prasugrel, and a combinationthereof.